title: Structural requirements for potent direct inhibition of human cytochrome P450 1A1 by cannabidiol: role of pentylresorcinol moiety.
abstract: Our recent work has shown that cannabidiol (CBD) exhibits the most potent direct inhibition of human cytochrome P450 1A1 (CYP1A1) among the CYP enzymes examined. However, the mechanism underlying this CBD inhibition remains to be clarified. Thus, to elucidate the structural requirements for the potent inhibition by CBD, the effects of CBD and its structurally related compounds on CYP1A1 activity were investigated with recombinant human CYP1A1. Olivetol, which corresponds to the pentylresorcinol moiety of CBD, inhibited the 7-ethoxyresorufin O-deethylase activity of CYP1A1; its inhibitory effect (IC50=13.8 µM) was less potent than that of CBD (IC50=0.355 µM). In contrast, d-limonene, which corresponds to the terpene moiety of CBD, only slightly inhibited CYP1A1 activity. CBD-2'-monomethyl ether (CBDM) and CBD-2',6'-dimethyl ether inhibited CYP1A1 activity with IC50 values of 4.07 and 23.0 µM, respectively, indicating that their inhibitory effects attenuated depending on the level of methylation on the free phenolic hydroxyl groups in the pentylresorcinol moiety of CBD. Cannabidivarin inhibited CYP1A1 activity, although its inhibitory potency (IC50=1.85 µM) was lower than that of CBD. The inhibitory effects of Δ(9)-tetrahydrocannabinol and cannabielsoin (IC50s ≈10 µM), which contain a free phenolic hydroxyl group and are structurally constrained, were less potent than that of CBDM, which contains a free phenolic hydroxyl group and is rotatable between pentylresorcinol and terpene moieties. These results suggest that the pentylresorcinol structure in CBD may have structurally important roles in direct CYP1A1 inhibition, although the whole structure of CBD is required for overall inhibition.
authors.affiliation: Department of Hygienic Chemistry, Faculty of Pharmaceutical Sciences, Hokuriku University, Kanazawa 920–1181, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Yamaori
authors.forename: Yoshimi
authors.initials: Y
authors.lastname: Okushima
authors.forename: Kazufumi
authors.initials: K
authors.lastname: Masuda
authors.forename: Mika
authors.initials: M
authors.lastname: Kushihara
authors.forename: Takashi
authors.initials: T
authors.lastname: Katsu
authors.forename: Shizuo
authors.initials: S
authors.lastname: Narimatsu
authors.forename: Ikuo
authors.initials: I
authors.lastname: Yamamoto
authors.forename: Kazuhito
authors.initials: K
authors.lastname: Watanabe
mesh_terms: D002185:Cannabidiol / Q000737:chemistry* / Q000494:pharmacology*; D019363:Cytochrome P-450 CYP1A1 / Q000037:antagonists & inhibitors* / Q000737:chemistry; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D011487:Protein Conformation; D012118:Resorcinols / Q000737:chemistry*; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D012118:Resorcinols; D002185:Cannabidiol; C569463:CYP1A1 protein, human; D019363:Cytochrome P-450 CYP1A1